Abstract Oropharyngeal candidiasis (OPC) causes significant morbidity in a large, diverse population, especially patients who are immunocompromised due to AIDS, neutropenia, diabetes mellitus, or the use of steroids. In fact, it is estimated that nearly 10 million cases of HIV/AIDS-associated OPC occur annually, and nearly a fifth of these individuals have esophageal involvement. Azole antifungal agents are the current mainstay of therapy for OPC. However, because of the emergence of azole resistance, it is critical to develop novel strategies to prevent and treat OPC. Our studies have focused on the hypothesis that C. albicans genes that promote adherence to and invasion of epithelial cells are critical for the organism to cause OPC. This hypothesis is based on the fact that invasion of the superficial epithelium occurs during OPC, and that biopsy specimens from OPC patients reveal organisms within oral epithelial cells. Adherence/invasion functions are carried out by cell surface proteins that interact with cognate receptors on host cells. These interactions enable the organism to invade oral epithelial cells and avoid being killed by phagocytes. Our data indicate that there are two adherence/invasion pathways that function in OPC. Pathway I includes the C. albicans surface proteins Als3 and Ssa1, which interact with the epithelial cell surface proteins epidermal growth factor receptor (EGFR) and HER2. Pathway II is newly described in our preliminary results. Pathway II includes the C. albicans surface protein Hyr1, which binds to the c-Met receptor tyrosine kinase on both oral epithelial cells and neutrophils. Our overall premise is that both Pathway I and Pathway II promote endocytosis of C. albicans by oral epithelial cells through E-cadherin. Pathway II also functions when C. albicans interacts with neutrophils to inhibit neutrophil killing. The objectives of the proposed studies are to test Pathway II function and its mechanistic basis, and to define the relationships between Pathway I and Pathway II. We will 1) determine the role of the Hyr1-c-Met interaction in inhibition of neutrophil fungicidal activity and epithelial cell invasion; 2) define the functional relationships among Hyr1 and the cell surface invasins Als3 and Ssa1 in vitro and in vivo; and 3) define additional Pathway I and II genes that function during OPC. The results from this research will provide new insight into the mechanisms by which C. albicans invades oral epithelial cells and down-regulates neutrophil fungicidal mechanisms. Not only will these data provide a deeper understanding of the pathogenesis of OPC, but they also hold promise to identify new potential drug and vaccine targets.